Association between abnormal uterine artery pulsatility index and the risk of fetal congenital heart defects: a hospital-based cohort study.

To explore the associations between high uterine artery pulsatility index (UtA-PI) values and congenital heart disease (CHD) risk and whether they differed between singleton and multiple pregnancies. This hospital-based cohort study involving 52,047 pregnant women who underwent prenatal examinations from 2012 to 2016. Infants born to the included pregnant women were followed until 42 days after birth to identify those with CHDs. Generalized estimating equations were used to estimate the associations of high right UtA-PI (> 95th percentile) values with maternal preeclampsia and fetal CHDs. Logistic regression analyses were conducted using path analysis models to quantify the effect of high right UtA-PI values on fetal CHD risk. A total of 42,552 women and 43,470 infants (147 with CHDs) were included. Preeclampsia risk was associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 3.01; 95% CI 2.57-3.52). CHD risk was marginally associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 2.26, 95% CI 1.03-4.95). Considering only two factors, 96.0% of the fetal CHD risk was mediated by preeclampsia in singleton-pregnant women, while 93.8% of the risk was related to a high right UtA-PI in multiple-pregnant women. A high right UtA-PI was marginally associated with an increased fetal CHD risk in singleton-pregnant women and might play an important role in multiple-pregnant women. Further studies are warranted to confirm these findings given the high loss to follow-up rate.

Chronic restraint stress increases social interaction in C57BL/6J mice monitoring through MiceProfiler analysis.

The social deficit is a prevailing symptom in stress-induced depression. Although social interaction behavior has been widely studied in humans and rodents, it is imprecise to record the social behavior between two free-moving mice via perusal. In the present study, we applied an approach to analyze the social behavior in mice using a software named "MiceProfiler." C57BL/6J mice were stressed via chronic restraint stress (CRS) and housed in three populations of different sizes as follows: single, three in a cage, and six in a cage. The MiceProfiler was used to analyze the video of behavioral repertoire and, the result showed that stressed and single housed mice exhibited more social interaction both in the contact time and contact activities. Furthermore, we investigated the effect of CRS on social behavior when the mice were housed in larger populations size (three or six in a cage) and found that, the CRS procedure promoted social interaction. However, the larger population size resulted in the less total contact time, less time of head-tail, and moving in an opposite way. Besides, the CRS mice showed less social avoidance while the mice from a larger population presented less active contact. And the CRS mice also exhibited a higher social hierarchy compared with the control. Our data indicated that mild restraint stress might increase the intercommunication between mice. Collectively, our findings provided a new evidence for social behavior study and the MiceProfiler could be a new tool to measure the social behaviors of rodents.

Profiling circular RNA in methamphetamine-treated primary cortical neurons identified novel circRNAs related to methamphetamine addiction.

Methamphetamine (METH) has been a worldwide health threat for years. Recent studies have reported that circular RNA (circRNA) are highly abundant and dynamically expressed in brain. However, connections between circRNA and METH-induced neurotoxicity remains indefinite. In the present study, primary cortical neurons were treated with METH in vitro. We profiled circRNA via high-throughput RNA sequencing and identified 2458 circRNAs. Bioinformatics analysis was performed to predict potential functions of these circRNAs which revealed several relevant pathways including 'morphine addiction' that may contribute to the pathogenesis of neuronal damage by METH. Especially, a METH-addicted mouse model was established with conditional place preference paradigm for validation of screened circRNAs. At last, we established co-expression networks of circRNAs with miRNAs and mRNAs to exhibit potential association among them. In conclusion, we firstly unveiled a role of circRNAs in METH-induced neuronal damage and METH addiction.

Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice.

Alcohol addiction can cause brain dysfunction and many other diseases. Recently, increasing evidences have suggested that gut microbiota plays a vital role in regulating alcohol addiction. However, the exact mechanism has not yet been elucidated. Here, our study focused on the intestinal bacteria alternations and their correlations with alcohol-induced neuropsychic behaviors. When consuming alcohol over 3-week period, animals gradually displayed anxiety/depression-like behaviors. Moreover, 16S rRNA sequencing showed significant intestinal microflora dysbiosis and distinct community composition. Actinobacteria and Cyanobacteria were both increased at the phylum level. At the genus level, Adlercreutzia spp., Allobaculum spp., and Turicibacter spp. were increased whereas Helicobacter spp. was decreased. We also found that the distances in inner zone measured by open field test and 4% (v/v) alcohol preference percentages were significantly correlated with Adlercreutzia spp. The possible mechanisms were explored and we found the expression of brain-derived neurotrophic factor (BDNF) and α1 subunit of γ-aminobutyric acid A receptor (Gabra1) were both decreased in prefrontal cortex (PFC). Especially, further correlation analyses demonstrated that decreased Adlercreutzia spp. was positively correlated with alcohol preference and negatively correlated with anxiety-like behavior and BDNF/Gabra1 changes in PFC. Similar relationships were observed between Allobaculum spp. and alcohol preference and BDNF changes. Helicobacter spp. and Turicibacter spp. were also correlated with PFC BDNF and hippocampus Gabra1 level. Taken together, our study showed that gut microbiota dysbiosis during chronic alcohol exposure was closely correlated with alcohol-induced neuropsychic behaviors and BDNF/Gabra1 expression, which provides a new perspective for understanding underlying mechanisms in alcohol addiction. © 2018 BioFactors, 45(2):187-199, 2019.

Torsion of normal-sized ovary during late pregnancy: A case report and review of the literature.

Adnexal torsion is one of the most common gynecologic surgical emergencies. All age groups can be affected, but torsion of normal-sized ovary that happens during late pregnancy is rare and challenging to be diagnosed. The objective of this article is to present a case of adnexal torsion in a normal-sized ovary suspected by magnetic resonance imaging (MRI) in the third trimester of pregnancy. A 36-year-old woman at 32 + 5 weeks gestational age was admitted to hospital due to recurrent severe left lower abdominal pain. Doppler ultrasound failed to demonstrate the ovarian diseases, while MRI scan suspected the diagnosis of adnexal torsion. The patient received emergent exploratory laparotomy, and the left adnexa with a necrotic ovary was removed. Tocolytic therapy was used before and after surgery. Finally, she delivered a healthy full-term infant via cesarean section. Adnexal torsion occurring in a normal-sized ovary was quite rare in the third trimester pregnancy. MRI might be better than ultrasound in the early diagnosis of ovarian torsion.

Melatonin protects against Aß-induced neurotoxicity in primary neurons via miR-132/PTEN/AKT/FOXO3a pathway.

Alzheimer's disease (AD) is a kind of neurodegenerative disorder associated with age. Investigations suggest that amyliod-ß (Aß) is implicated in the pathogenesis of AD. The accumulation of Aß in the brain causes oxidative stress and synaptic toxicity, leads to synaptic dysfunction and neuronal death. Previous investigations suggest that melatonin an endogenous hormone can counteract Aß-induced neurotoxicity. However, the molecular mechanisms of Aß-induced toxicity and melatonin treatment remain elusive. Studies indicate that microRNA-132 is crucial for neuronal survival and plays a key role in the pathological process of AD. Moreover, PTEN and FOXO3a two key targets of miR-132 are upregulated in the AD brain. Here, we exposed the primary cultured cortical neurons with Aß25-35 and treated with melatonin. Our investigations demonstrated that Aß25-35 exposure significantly decreased the expression of miR-132 and elevated the expression of PTEN and FOXO3a. Whereas, melatonin treatment could rescue the expression of miR-132 and downregulate the level of PTEN and FOXO3a. Moreover, melatonin blocked the nuclear translocation of FOXO3a and thereby suppressed its pro-apoptotic pathways. In addition, our investigations suggested that the over-expression of miR-132 could block Aß-induced neurotoxicity. We also found that VO-OHpic (PTEN inhibitor) could counteract Aß-induced neuronal damage, and LY294002 (AKT inhibitor) suppressed the protective effect of melatonin. Together, these results indicate that melatonin exerts its neuroprotective effect in Aß-induced neurotoxicity via miR-132/PTEN/AKT/FOXO3a pathway. © 2018 BioFactors, 44(6):609-618, 2018.

Resveratrol Suppresses Rotenone-induced Neurotoxicity Through Activation of SIRT1/Akt1 Signaling Pathway.

Rotenone is a common pesticide and has been reported as one of the risk factors for Parkinson disease. Rotenone can cause neuronal death or apoptosis through inducing oxidative injury and inhibiting mitochondrial function. As a natural polyphenolic compound, resveratrol possesses the antioxidant capacity and neuroprotective effect. However, the mechanism underlying the neuroprotective effect of resveratrol against rotenone-induced neurotoxicity remains elusive. Here, we treated PC12 cells with rotenone to induce neurotoxicity, and the neurotoxic cells were subjected to resveratrol treatment. The CCK8 and LDH activity assays demonstrated that resveratrol could suppress neurotoxicity induced by rotenone (P < 0.01). The DCFH-DA assay indicated that resveratrol reduced the production of reactive oxygen species (ROS). JC-1 and Hoechst 33342/PI staining revealed that resveratrol attenuated mitochondrial dysfunction and cell apoptosis. Moreover, resveratrol reversed rotenone-induced decrease in SIRT1 expression and Akt1 phosphorylation (P < 0.05). Furthermore, when the SIRT1 and Akt1 activity was inhibited by niacinamide and LY294002, respectively, the neuroprotective effect of resveratrol was remarkably attenuated, which implied that SIRT1 and Akt1 could mediate this process and may be potential molecular targets for intervening rotenone-induced neurotoxicity. In summary, our study demonstrated that resveratrol reduced rotenone-induced oxidative damage, which was partly mediated through activation of the SIRT1/Akt1 signaling pathway. Our study launched a promising avenue for the potential application of resveratrol as a neuroprotective therapeutic agent in Parkinson disease. Anat Rec, 301:1115-1125, 2018. © 2018 Wiley Periodicals, Inc.

Paliperidone increases spontaneous and evoked firing of mesocortical dopaminergic neurons by activating a hyperpolarization-activated inward current.

Mesocortical dopaminergic (DA) subtype neurons specifically project to the prefrontal cortex, which is closely related with schizophrenia. Mesocortical DA neurons have unique physiological characteristics that are different from those of mesostriatal and mesolimbic DA neurons. Paliperidone, an atypical antipsychotic, is currently used to treat schizophrenia and has better therapeutic effects than typical antipsychotics. However, the underlying physiological mechanism remains unclear. To explore the effects of paliperidone on mesocortical DA neuron activity, here, we retrogradely labeled these cells with fluorescent microsphere retrobeads, and the electrophysiological changes were recorded in whole-cell recordings in rat midbrain slices with or without paliperidone. The data showed that paliperidone (20µmol/L) increased the spontaneous firing rates of labeled mesocortical neurons (P<0.05). Moreover, paliperidone also increased the frequency of evoked action potentials by current injection stimulation (P<0.05), whereas the accompanying amplitude decreased. Furthermore, to explore the mechanisms of paliperidone's effect, Ih currents were detected, and the results showed that hyperpolarizing voltage pulses evoked instantaneous Ih inward currents and paliperidone increased the maximum Ih current. In addition, paliperidone decreased the spontaneous inhibitory postsynaptic currents. Thus, paliperidone increased the spontaneous and evoked firing of mesocortical neurons, possibly by activating the Ih inward current and reducing the inhibitory synaptic transmission, which provides an underlying mechanism of paliperidone's application in schizophrenia.

Roles of NAD in Protection of Axon against Degeneration via SIRT1 Pathways.

Axonal degeneration is a common pathological change of neurogenical disease which often arises before the neuron death. But it had not found any effective method to protect axon from degeneration. In this study we intended to confirm the protective effect of nicotinamide adenine dinucleotide (NAD), investigate the optimal administration dosage and time of NAD, and identify the relationship between silence signal regulating factor 1 (SIRT1) and axonal degeneration. An axonal degeneration model was established using dorsal root ganglion (DRG) neurons injured by vincristine to observe the protective effects of NAD to the injured axons. In addition, the potential contribution of the SIRT1 in axonal degeneration was also investigated. Through the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunochemistry staining, axons counting and length measuring, transmission electron microscope (TEM) observation, we demonstrated that NAD played an important role in preventing axonal degeneration. Further study revealed that the expression of SIRT1 and phosphorylated Akt1 (p-Akt1) was up-regulated when NAD was added into the culturing medium. Taking together, our results demonstrated that NAD might delay the axonal degeneration through SIRT1/Akt1 pathways.

Striatal extracts promote the dopaminergic differentiation of GFP-bone mesenchymal stem cells.

Bone mesenchymal stem cells (BMSCs) are an attractive donor graft source because of the potential of self-renewal and multi-direction differentiation. However, it is a great challenge to induce BMSCs to specifically differentiate to dopamine (DA) neurons for the treatment of Parkinson's disease. Because the striatum is the target tissue for the projection of DA neurons in the midbrain, we investigated whether its extracts could promote the dopaminergic differentiation of BMSCs. BMSCs were isolated from green fluorescent protein (GFP) transgenic mice. Flow cytometry was used to identify the expression of CD29 and CD11b in cultured BMSCs; and immunochemical staining was employed to determine the differentiation of BMSCs. Our results showed that striatal extracts could induce differentiation of BMSCs into both neurons and glia, especially the DA neurons. When transplanted to the rat striatum, GFP-BMSCs could differentiate into tyrosine hydroxylase positive neurons and demonstrate potential migration in the brain. Taking together, our results suggest that striatal extracts can specifically promote the dopaminergic differentiation of GFP-BMSCs, thereby providing a feasible strategy for the treatment of Parkinson's disease.

TNF-α increases bone marrow mesenchymal stem cell migration to ischemic tissues.

The objective of this study was to analyze the influence of TNF-α on rat mesenchymal stem cells (MSCs) and to assess feasibility of MSC transplantation to repair ischemic injury. In this study, adhesion molecules and cell specific surface markers on MSCs were measured after exposure to different concentrations of TNF-α. MSCs stimulated with varying concentrations of TNF-α were cultured with aortic endothelial cells, and the adhesion rate was measured. MSCs were then stimulated with an optimum concentration of TNF-α as determined in vitro, and injected intravenously into rats with ischemic hind limb injury. The number of MSCs in muscle samples from the ischemic area was counted. The results showed that (1) TNF-α induced a concentration-dependent increase in VCAM-1 expression in MSCs, whereas the expression of L-selectin, ICAM-1 and VLA-4 did not change significantly. Expression of MSC-specific antigens was unchanged. (2) MSCs pretreated with 10 ng/ml TNF-α showed significantly increased adhesion to endothelial cells in vitro, and accumulated to a greater extent in the areas of ischemic damage in rat hind limbs. We were able to conclude that TNF-α has no effect on expression of MSC-specific markers, but can increase the expression of VCAM-1 on rat MSCs. Suitable concentrations of TNF-α can promote MSC adhesion to endothelial cells and migration to damaged tissue.

Neuroprotective effects of Buyang Huanwu decoction against hydrogen peroxide induced oxidative injury in Schwann cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu decoction (BYHWD) is a traditional Chinese medicine and can be used to promote peripheral nerve regeneration. However the regenerative mechanism of BYHWD remains unclear. The objective of this study was to investigate the protective mechanisms of BYHWD in Schwann cells damaged by hydrogen peroxide (H(2)O(2)). MATERIALS AND METHODS: Schwann cells which were derived from neonatal sciatic nerves of rats were used in subsequent experiments. Schwann cells were injured by various concentrations of H(2)O(2) (0.25, 0.5 and 1mM final concentration). BYHWD (600 µg/ml final concentration) was added to the medium either simultaneously or 1h later after the addition of H(2)O(2). Subsequently, methyl thiazolyl tetrazolium (MTT) assay was performed. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were also examined after 12h. The expression of Caspase 3 and the concentration of intercellular Ca(2+) ([Ca(2+)]i) were also determined. RESULTS: Among three concentrations of H(2)O(2), 0.5mM H(2)O(2) induced Schwann cells swelled and neuritis disappeared after 12h. In the presence of BYHWD, MTT assay showed that more cells were viable in comparison with the H(2)O(2) injury group. Moreover, the addition of BYHWD has also increased the SOD activity with decreased in MDA level. Furthermore, the concentration of [Ca(2+)]i and expression of Caspase 3 were decreased with the addition of BYHWD in culture. CONCLUSIONS: Our results revealed that BYHWD protected Schwann cells from oxidative injury. The mechanism of BYHWD promoting neural regeneration possibly associated with its anti-oxidative activity.